1. Field of the Invention
The present invention relates to a method for separating poly(vinyl acetate) microspheric particles, and to the microspheric embolic particles of a dual structure consisting of poly(vinyl acetate) core (PVAc core) and poly(vinyl alcohol) shell (PVA shell), which is prepared from said separated Poly(vinyl acetate) particles. More particularly, the invention relates to a method for separating poly(vinyl acetate) particles having various particle sizes, which have been prepared by suspension polymerization of vinyl acetate monomers, into individual microspheric poly(vinyl acetate) particles with uniform particle size distribution by the use of inorganic salt as a dispersing and antistatic agent, to a method for preparing the microspheric embolic particles of a dual structure consisting of PVAc core and PVA shell by suspending the separated poly(vinyl acetate) particles into an aqueous alkali solution and subjecting the suspended particles to a heterogeneous surface saponification, and to the microspheric embolic particles thus prepared.
2. Description of the Prior Art
Embolotherapy is a medical treatment technology that blocks the blood flow in blood vessels which supply blood for lesions of surgically untreatable sites by injecting a special material into said blood vessels, and thereby treats the lesions, relieves symptoms due to excessive blood flow and prevents hemorrhaging during surgical operations. Said special material is referred to as "embolic material." Poly(vinyl alcohol) (PVA) is currently used in commerce as embolic materials. Embolotherapy is used as a means of treatment for hypervascular tumors with high vascularity, vascular diseases such as arteriovenous malformation (AVM), and traumatic or inflammatory hemorrhaging, such as with tuberculosis.
J. Markowitz first established the concept of treating diseases by embolotherapy in 1952. He suggested a treatment method for hepatic tumors by blocking arterial blood flow, based on the fact that the liver is supplied with blood via both hepatic portal vein and hepatic artery, while the primary and metastatic hepatic tumor cells mainly via hepatic artery (See J. Markowitz, Surg. Bynecol. Obstet., 395, 644, 1952).
For selective embolization, it is necessary to know whether the hepatic tumor cells are supplied with blood via hepatic portal vein or hepatic artery. Hearley and Sheena have ascertained by means of injecting dyes and radioactive material that hepatic tumor cells are supplied with blood solely from the hepatic artery (See J. E. Hearley and K. S. Sheena, et al., S Surg. Forum, 14, 121, 1963). Further, Gelin et al. have showed that after removing the hepatic artery, the blood flow in the malignant tumors decreased by 90%, whereas the blood flow in normal tissues decreased only by 35-40% (See L. E. Gelin, D. H. Lewis and L. Nilsson, Acta Hepatosplenol, 15, 21, 1968).
Embolotherapy is used in the treatment of AVM addition to liver cancer. There is a report showing that embolotherapy to the cerebral AVM resulted in an increase in the survival rate (See L. A. Nisson and L. Zettergen, Acta Pathol. Microbiol. Scand., 71, 187, 1967).
Further, recent studies have shown that in addition to said lesions, uterine arterial embolotherapy is effective for the treatment of hemorrhaging and pelvic pains (See S. C. Goodwin, S. Vedantham, B. Mclucas, A. E. Fomo and R. Perrella, J. Vascular and Interventional Radiology, 8(4), 517, 1997). There is also a report showing that embolotherapy can be used to prevent excessive hemorrhaging during surgical operations, to shorten the required time for surgery and to reduce risks in an operation by pre-operatively occluding blood vessels around injuries (See T. Tikkakoski, J. Luotonen, S. Leinonen, T. Siniluoto, O. Heikkila, M. Paivansalo and K. Hyrynkangas, LARYNGOSCOPE 107(6), 821, 1997).
There are a variety of materials that are used as embolic materials, including metallic fibrous coils, liquid tissue adhesives, that is in liquid forms upon operation, but after administration is hardened to occlude blood vessels, barium impregnated silastic balls, methacrylates, collagen-coated acrylic microspheres and PVA. Since the 1970s, especially the PVA in the form of particulates and hydrogel has been widely used as an embolic material.
An ideal embolic material should be made of a substance that exhibits excellent biocompatibility due to the interaction with tissues surrounding the site to be treated; be standardized in the physical sizes and the distribution of particles sizes so as to effectively get to the target site of lesions in order to achieve an excellent therapeutic effect and to predict therapeutic effects; be smooth on the surface so as not to induce secondary lesions such as inflammation in the occluded blood vessels; be easily handled and injected for general clinical use; exhibit permanent embolic effects without reperfusion of the blood; and have X-ray radiopacity or form homogeneous suspension in a nonionic vehicle for correct evaluation of the occlusions of the blood vessels upon and after the operation.
Poly(vinyl alcohol) (PVA), which was first prepared by Herrmann and Haehnel of Germany in 1924 (See W. O. Herrmann and W. Haehnel, German Patent 450,286, 1924), is a linear, crystalline, hydroxy group-containing polymer prepared by saponification of vinylester-based polymers such as poly(vinyl acetate). PVA has been singled out from among a variety of embolic materials because of its biocompatibility, technical ease and because its particle size can be variously adjusted. Considering the above-mentioned requirements, it can be easily understood that among others, PVA in a microspheric shape with uniform dimension distribution is most ideal for embolic materials.
At present, PVA is used as an embolic material for malignant hepatic tumors, hepatic AVM, cerebral AVM, vascular tumors in many sites, etc., and is the most widely used among currently existing embolic materials. Accordingly, a lot of studies on poly(vinyl alcohol) are in progress.
However, the use of poly(vinyl alcohol) in existing studies and in clinics has been reported to cause side effects such as inflammation of the embolized blood vessel. This inflammation is thought to be caused by the sharp-edged portions of the materials used. Moreover, with respect to the size of embolic particles, neonates have been reported to die after their AVMs have been treated with commercial embolic poly(vinyl alcohol). The results of a study on the uniformity of the particle sizes of commercial embolic poly(vinyl alcohol) particles illustrate that the death of neonates is related to the non-uniformity of the particle sizes (See I. Repa, et al., Radiology, 170, 395, 1989).
Although the commercial poly(vinyl alcohol) products that are currently being widely used as embolic materials, such as Contour (registered trademark), Embosphere (registered trademark), Ultra Drivalon (registered trademark), etc., have been found to have a very low uniformity of particle sizes. Although high quality commercial products have been said to have size distribution ranges of 50-150 .mu.m, 150-250 .mu.m, 250-350 .mu.m and 350-550 .mu.m, it is reported that they, in fact, have a non-uniform physical size distribution, such as a particle size of from 1 .mu.m to 1400 .mu.m or larger.
Furthermore, as can be seen from the scanned electron micrograph that is shown in FIG. 1, the commercial poly(vinyl alcohol) embolic material "Contour" is very rough, has sharp surfaces and, therefore, is very different from spherical particles having a uniform dimension distribution.
Many researchers have recently made attempts to prepare spherical particles from various polymers other than poly(vinyl alcohol), such as porous cellulose, gelatin, collagen and collagen-coated acrylate, in order to develop ideal microspheric embolic materials. However, it is impossible to control the chemical dimensions (e.g. molecular weight, molecular weight distribution and branching degree) and physical dimensions (particle size and shape) of natural occurring polymeric materials such as gelatin, because these materials are obtained directly from nature. Additionally, it is difficult to make spherical particles of variable sizes into a uniform size distribution with a view to operating. Also, their permanent embolic effects have not yet been confirmed.
Consequently, established studies on embolic materials have found that poly(vinyl alcohol) is the most effective. However, there is no report that shows the preparation of microspheric particles with a uniform size distribution by means of controlling the synthesis conditions of poly(vinyl alcohol) itself (e.g., polymerization condition of precursors) or molecular variables (e.g., molecular weight, saponification degree, branching degree, stereoregularity, etc.).
Also, although the polymeric particles prepared by suspension polymerization are generally retained in spherical forms, their sizes are very different depending on the condition of polymerization. Further, it is very difficult to separate them into individual, uniform-sized particles because they associate due to static attractive forces between the suspending agents used during polymerizing and the particles. The same problems occur when poly(vinyl acetate) is prepared by means of suspension polymerization of vinyl acetate. Thus, when it is converted to PVA by the saponification, the PVAc particles are retained in spherical forms but their sizes are non-uniform, and thereby the particles are inevitably associated. Therefore, it is necessary to separate the precursor spherical poly(vinyl acetate) in order to prepare PVA particles as excellent embolic materials with high quality.
Generally, the saponification of the poly(vinyl acetate) for the preparation of poly(vinyl alcohol) is achieved by completely dissolving poly(vinyl acetate) in methanol and then dropping the alkali solution. The poly(vinyl alcohol) prepared as such has very irregular surface and very wide size distribution.
Recently, the poly(vinyl acetate) has been sometimes used as embolic particles (See Y. Uchiyamatsuyuki, K. Kawashima, H. Araki and S. Otomo, Pharmacology Biochem, Behavior, 52(3), 555, 1995), but it is not accepted in terms of its biosynthesis and is not widely used clinically Thus, to produce the embolic particles with excellent embolic ability, a new saponification method that can prohibit the association of particles with maintaining the shape of particle is needed.
The present inventors have intensively investigated methods for separating the poly(vinyl acetate) particles which have been prepared by means of suspension polymerization, and methods for producing the poly(vinyl alcohol) embolic materials by the saponification of the poly(vinyl acetate). We have found that poly(vinyl acetate) particles having various particle sizes, which have been prepared by suspension polymerization of vinyl acetate monomers, can be separated into respective poly(vinyl acetate) particles with uniform particle size distribution by the use of inorganic salt as a dispersing and antistatic agent, and that the resulting separated poly(vinyl acetate) particles can be saponified solely on the surface thereof, with the microspheric forms thereof maintained, by suspending the particles in an aqueous alkali solution and subjecting the suspended particles to a heterogeneous surface saponification, thereby the novel microspheric embolic particles of a dual structure consisting of poly(vinyl acetate) core/poly(vinyl alcohol) shell can be prepared.